This competitive renewal investigates the mechanisms and significance of dopaminergic (DA) and serotonergic (5HT) neurotransmission systems in Tourette's syndrome (TS) using PET neuroreceptor imaging which should provide a more complete understanding of pathophysiology and possible treatments. Our recruitment strategies have focused on completing our original DA and 5HT measure sample size, originally funded for only 45% at Year 1 of this R01. We now request funds to complete this sample size given that we have substantial progress including (1) sustained elevations of dopamine release (DArei) with a new PET scanner which is a reproduction of our published paper, (2) demonstrate reductions in SERT in our TS subject, (3) uniquely carrying out amphetamine induced DArei in TS but also pre synaptic DA transporters (DAT) and receptor density (D2Bmax) in the same individuals, (4) similarly also studying both serotonin transporters (SERT) and 5HT2A receptors in the same subjects. Completion of the sample will determine what the inter-relationships are between these pre, post and intra synaptic measures for dopamine and for serotonin transporters and postsynaptic receptors in TS. In addition to our findings in TS alone, we have found an interesting contrast between TS subjects with and without co-morbid OCD (TS + OCD). In particular we found that TS + OCD had elevated DArei compared to TS - OCD and both elevated compared to controls. We found a significant decline in SERT in midbrain in 9 TS + OCD vs. 2 TS - OCD with trends for elevations for TS + OCD vs. TS - OCD for 5HT2A. In 3 subjects who had both DA and 5HT measures, we found correlations between SERT, DArei and 5HT2A which along with the DA and 5HT group differences were suggestive of the co-morbid effect of OCD in TS. This suggested that lower intrasynaptic 5HT resulted in elevated DArei and 5HT2A and lower SERT in these subjects. Further evaluation in AIM 4 with both DA and 5HT measures will help us directly test the hypothesis about the role of 5HT in modulating our tonic/phasic DA model of TS by additionally incorporating features of OCD. At the end of this renewal, we will have completed our originally funded AIMS and examined new possibilities of 5HT and DA interrelationships and role of co morbid OCD and TS.